Vascular endothelial σ1-receptor stimulation with SA4503 rescues aortic relaxation via Akt/eNOS signaling in ovariectomized rats with aortic banding

Hideaki Tagashira, Takayuki Matsumoto, Kumiko Taguchi, Chen Zhang, Feng Han, Keiko Ishida, Shingo Nemoto, Tsuneo Kobayashi, Kohji Fukunaga

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Background: We previously reported that σ1-receptor (σ1R) expression in the thoracic aorta decreased after pressure overload (PO) induced by abdominal aortic banding in ovariectomized (OVX) rats. Here, we asked whether stimulation of σ1R with the selective agonist SA4503 elicits functional recovery of aortic vasodilation and constriction following vascular injury in OVX rats with PO. Methods and Results: SA4503 (0.3-1.0 mg/kg) and NE-100 (a σ1R antagonist, 1.0 mg/kg) were administered orally for 4 weeks (once daily) to OVX-PO rats. Vascular functions of isolated descending aorta were measured following phenylephrine (PE)- or endothelin-1 (ET-1)-induced vasoconstriction and acetylcholine (ACh)- or clonidine-induced vasodilation. SA4503 administration rescued PO-induced σ1R decreases in aortic smooth muscle and endothelial cells. SA4503 treatment also rescued PO-induced impairments in ACh- and clonidine-induced vasodilation without affecting PE- and ET-1-induced vasoconstriction. Ameliorated ACh- and clonidine-induced vasodilation was closely associated with increased Akt activity and in turn endothelial nitric oxide synthase (eNOS) phosphorylation. The SA4503-mediated improvement of vasodilation was blocked by NE-100 treatment. Conclusions: σ1R is downregulated following PO-induced endothelial injury in OVX rats. The selective σ1R agonist SA4503 rescues impaired endothelium-dependent vasodilation in the aorta from OVX-PO rats through σ1R stimulation, enhancing eNOS-cGMP signaling in vascular endothelial cells. These observations encourage development of novel therapeutics targeting σ1R to prevent vascular endothelial injury in vascular diseases.

Original languageEnglish
Pages (from-to)2831-2840
Number of pages10
JournalCirculation Journal
Volume77
Issue number11
DOIs
Publication statusPublished - 2013

Keywords

  • Endothelial nitric oxide synthase
  • Vascular disease
  • σ1-receptor

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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